Bacteria have the ability to generate resistance to antibiotics through lateral gene transfer, mutation of enzymes, or the expression of enzymes which actively pump the antibiotic out of the cell or break it down. Over the past 10 years, resistance to existing antibiotics has become a significant problem. Vancomycin is currently the drug of last resort to combat multidrug-resistant Gram-positive bacteria. In many places vancomycin-resistant Staphylococcus aureus and Enterococci (VRE) have been discovered. There is thus a desperate need for new antibiotics to replace this drug of last resort.
A host of cytoplasmic targets have been used in the development of new antibiotics, such as gyrase inhibitors, protein synthesis inhibitors, muramyl cascade inhibitors, and many more. The major hurdle in designing such drugs is that in addition to enzyme based activity these drugs need to cross the bacterial cell wall to exert their antibacterial effect. On the other hand, enzymes involved in synthesis of the bacterial cell wall exist on the cell wall exterior, and therefore drugs inhibiting these enzymes can exert their bactericidal or bacteriostatic effect without having to cross the cell wall. For example, penicillins, cephalosporins, and moenomycin are antibiotics that interact with bacterial transpeptidase enzymes. Vancomycin does not interact with bacterial transpeptidase enzymes, but rather sequesters the substrate of the enzyme.
Moenomycin is a natural product that directly inhibits the synthesis of bacterial peptidoglycan (PG). The biological activity of moenomycin is remarkable compared with that of most other natural antibiotics: it is 10-1000 times more potent than vancomycin against Gram-positive organisms. See, e.g., Ostash and Walker, Curr. Opin. Chem. Biol. (2005) 9:459-466; Goldman et al., Curr. Med. Chem. (2000) 7:801-820. Structure-activity relationship studies of moenomycin analogs conducted on the saccharide portion of the molecule have revealed that moenomycin analogs with at least three carbohydrate units (C, E, and F) are active in vivo against Gram-positive bacteria. See, e.g., Garneau et al., Bioorganic & Medicinal Chemistry (2004) 12:6473-6494. Furthermore, while the phosphoryl group and the carboxylate group of the phosphoglycerate linker are now considered important for bioactivity, the moenocinol chain is also considered to be an important structural component of the molecule and probably contributes to target binding both by direct interactions with the hydrophobic funnel that leads to the membrane and by membrane anchoring. See, e.g., Fuse et al., Chemical Biology (2010) 5:701-711. However, at the same time, the moenocinol chain is also credited with poor pharmacokinetic properties and high serum binding of meonomycin, e.g., its absorption upon oral administration is relatively poor. See, e.g., van Heijenoort, Glycobiology (2001) 11:25 R-36R.
